8-aminotropanium compounds



nitcd States 2,948,730 .s-AMINOTROPAMUM COMPOUNDS No Drawing. Filed Feb.4, 1959, Ser. No. 791,033

8Claims. (omen-492) This invention relates to derivatives of naturallyoccurring and synthetic alkaloids. In one specific iaspect, it relatesto a new class of physiologically active quaternized hydrazinium salts,the chloramine .adducts of tr-opane and its derivatives. In anotherspecific aspect, it relates to compositions useful as intermediates inthe preparation of pharmacologically active compounds.

Oxygenated derivatives of tropane occur in nature in the roots andleaves of solanaceous plants, for example, in the atropa belladonna,henbane and thornapple. Atropa belladonna, frequently referred to asnightshade, contains the alkaloid hyoscyamine, C1qH23NO3. Hyoscyamine, auseful pharmaceutical, racemizes rapidly in the presence of dilutealkalies or slowly on standing Zinto atropine, likewise a usefulpharmaceutical. Atropine is used in medicines to dilate the pupil of theeye and may be applied either externally or internally. Externally, 1part in 130,000 parts of water exerts a notable effect. Internally, aslittle as 0. 1 g. is poisonous.

When heated in the presence of :a base atropine splits into thesecondary alcohol, tropin'e and the acid, tropic acid. Tropine is atertiary base as well as an alcohol, and tropic acid is an aromatichydroxyacid. .See Equation 1 below.

Many of the simple derivatives of .trop'ane exist in variousstereoisomeric forms. Substitution may generate asymmetric carbon atomsand optical activity can result. The maximum number of optical isomerstheoretically possible is.2 where n islthe nuniber of asymmetric carbonatoms. Not allot the ipos's'ible' isomers exist because of the"geometric requirements ottused ring systems. There aretwo'3-hydroxytropanes, tropinc and pseudotropine, which dififer onlyinthe cisor trans discovered a generic class of hydrazinium compoundslocation of the hy'clroxyl substituent with respect-to the N-methylgroup. Tropine and pseudotropine each have a plane of symmetry and areconsequently optically inactive despite the fact they contain a carbonatom with four diiferent substituents. When tropine is esterified withdl-tropic acid, the product is atropine. This reaction is the reverse ofthe hydrolysis shown in Equation 1 above.

Another common tropane derivative, cocaine, is obtained from the leavesof the coca shrub in Peru and Java. Cocaine is a local anesthetic,especially usedin eye, nose and throat surgery. Because of its ratherhigh toxicity and habit-forming properties, it has been replaced in someof its uses by such synthetic local anesthetics as procaine andbutyn.Cocaine melts at 98 C.; it is crystalline and levorotatory. It is adicster of levoecgonine as shown below in Equation 2. e

Other we'll-known compounds'and members of this -alkaloidfamily includemetelo'idine (from datura plants),

scopolamine (from 'hyoscyamus plants), tropinone, .scopine andscopoline. In addition to the uses described hereabove, tropanealkaloids are efiective as mydriaties, cycloplegics, and as cerebralsedatives in treating motion sickness and the like. Hyoscyamine finds aspecific application in relieving symptoms of Parkinsons' disease.

By treating tropane and its derivatives with chloramine, we havediscovered new classes of hydrazinium salts having remarkablepharmacological properties and mitigated toxicity. p p 7 It is theobjectof the present invention to provide a new generic class ofhydraziniumsalts useful as pharmaceuticals and as pharmaceuticalintermediates, This application is a continuation-impart of our copending application Serial No. 689,779, filed October 14, 1957. Inaccordance with the present invention, we have corresponding to theformula:

In the above formula, .R and R takenindividuallyare hydrogen but takencollectively are ethereal oxygen co npleting the oxirane ring. R takenalone maybe hydroxyl, phenoxy or diphenalkoxy. R may be takencollectively with R to complete a carbonyl oxygen. In

addition to completing the carbonyl group with R R the primary activityof our novel compounds resi'des -1n I the cation. The salts obtainedthrough ,thevvariati or A may in some cases have special advantagesfdueto solubility, ease of crystallization, lack of objectio P 0 taste andthe like, but these considerations are all sidiary to thecharacteristics of the cation hid! are r independent of the character ofA". Hence all variations of A- are considered equivalent for the purposeof the present invention.

Specific, but nonlimiting, variants of the anion A- are as follows:chloride, bromide, iodide, sulfate, bisulfate, acetate, salicylate,valerate, oleate, phenate, laurate, borate, benzoate, lactate, nitrate,diglycollate, phosphate,

imino-tris-acetate, phenylethylbarbiturate, acid phosphate,

o-acetoxybenzoate, citrate, diallylbarbiturate, sulfathiazole,theophyllinate, urate, adipate, maleate, fumarate, succinate, tartrate,diethylbarbiturate, penicillinate, guaiacolsulfonate,methylene-bis-cresotinate, camphorate, salicylamide, diphenylhydantoin,carbonate, cacodylate, aconitate, polymethacrylate,poly(styrenesulfonate), phytate sulfamate, gentisate, malate and thelike.

In preparing the compounds of the present invention, it is usuallysuitable to contact chloramine with a solution of the basic tropanederivative, allow the reaction to proceed until the desired quantity ofchloramine is consumed, and then isolate and purify the resultanthydrazinium chloride by standard laboratory techniques. While chloramineis most advantageously prepared in a form of a gaseouschloramine-ammonia-nitrogen stream obtained from a generator constructedaccording to the teachings of Sisler et al., US. Patent 2,710,248, othermethods are equally adaptable for the purposes of the present invention.For instance, chloramine can be made by reacting chlorine with an excessof ammonia in carbon tetrachloride solution or similar halogenatedhydrocarbon solvent under controlled conditions of mixing at lowtemperatures. Such a procedure is fully described in US. Patent No.2,678,258, to John F. Haller. Another effective procedure is that ofColeman et 'al. fully described in Inorganic Syntheses, vol. I, 59(1939). Alternatively, the chloramine can be formed in the presence ofthe amine as described in copending application S.N. 605,230, filedAugust 20, 1956, which teaches the reaction of chlorine and a tertiaryamine in the presence of excess ammonia. For simplicity, when both thebase and product are soluble in the same inert solution, e.g.,chloroform, We may form chloramine in situ by this method in thesolution containing the tropane derivative.

The choice of solvent is one of economy and simplicity. For goodabsorption (and therefore reaction) it is desirable to bubblechloroamine through a long column of a solution comprising the tropanederivative dissolved in a relatively cheap inert solvent. Solvents whichserve this purpose include hydrocarbons, e.g., heptane, cyclohexane,benzene, xylene and the like; ethers, e.g., diethyl ether, diamyl ether,dioxane and anisole; amides, e.g., dimethylformamide anddimethylacetamide; halohydrocarbons, e.g., chloroform, carbontetrachloride, trichlorethylene, and chlorobenzene; nitroaromatics,e.g., nitrobenzene. For special purposes, water and other hydroxylicsolvents such as ethanol and Cellosolve may be used.

Tropane derivatives suitable for chloramination include, but are notlimited to, the following: tropane, tropine, pseudotropine, tropidine,3,7-dihydroxytropane, 6,7-dihydroxytropane, 3-chlorotropane, tropineacetate, pseudotropine benzoate, scopine, scopoline, ecgonine,meteloidine, scopolamine, atropine, atroscine, homotropine, hyoscyamine,apoatropine, teloidine, anhydroecgonine, cocaine, cinnamoylococaine,tropacocaine,

turxilline, psicaine, cocaine, ecgonidine, benzoylecgonine,

tropine diphenylacetate, tropine benzilate,p-chlorobenzhydryloxytropane, 3,6,7-triacetoxytropane, convolvamine,methylscopoline, scopoline butyrate, and the like.

It should be further noted that for purposes of the present inventionthe above compounds can be used directly or as mixtures. Naturalmixtures maybe chloraminated as such. For example, belladonna extractcontains mixed atropine, atrocine, hyoscine and hyoscyamine, the extractof Javanese leaves of erythroxylon 4 coca contain cocaine,benzolyecgonine, methylecgonine, truxilloeocaine and coeamine.

It is obvious that chloramination gives only the chloride derivative. Toprovide the other useful tropane hydrazinium salts of the presentinvention, it is necessary, by metathesis, to prepare salts of otheranions. It is possible to make mixed anion salts by adding, for example,the hyoscyamine chloramine adduct to a standard sulfa mixture, e.g.,sulfamerzine, sulfamethazine and sulfadiazine to obtain a mixture of thethree salts. Many of the anions described supra can be obtained bymixing aqueous solutions of the hydrazinium chloride with appropriatereagents. More often than not, the desired product precipitates directlyas the reaction progresses. Certain of the organic salts can be moreconveniently made in aqueous alcohol solutions or in other polarsolvents. Chloroform is particularly suitable for preparing stearatesand other fatty acid derivatives. In fact, it is possible to carry outcertain metathetical reactions in the absence of any solvent at all. Themethod chosen is naturally dependent on the physical properties of thedesired salt. When it is necessary to prepare a very soluble salt, thereaction of the hydrazinium hydroxide with the appropriate acid may beutilized. Subjecting a hydrozinium halide to the action of moist silveroxide will give the hydroxide.

The scope and utility of the present invention is further illustrated bythe following examples.

Example I A chloramine generator was constructed according to theteachings of Sisler et al., supra. The generator consists of ahorizontal Erlenmeyer flask, the bottom of which contains an outlet tubewhich is directed into the reactor containing a solution of alkaloid.Ammonia and chlorine (which may be diluted with nitrogen) are introducedseparately into the top of the flask through concentric conduits, theinner tube carrying the chlorine. Chloramine and ammonium chloride areformed in the flask at the point where the chlorine and ammonia vaporscome into contact. A rod is provided in the chlorine inlet stream toprevent any plugging of that stream with ammonium chloride. The outletend of the flask is masked with glass wool to collect any ammoniumchloride which otherwise would be carried into the reactor. Thechloramine yield for any one set of gas flow meter readings isdetermined by removing the reactor and passing the filtered chloraminestream directly into a series of three chilled traps. Under theconditions of chloramine generation, only ammonia, chloramine, andnitrogen can pass through the glass wool into the traps. Since the trapsare maintained at at least 70 C., the ammonia and chloramine condensetherein and react relatively slowly (compared to the chlorine-ammoniareaction velocity) to form hydrazine, nitrogen and ammonium chloride. Byallowing the low temperature condensate to come to room temperatureslowly, the chloramine is converted quantitatively to nonvolatile (at2030 C.) ammonium chloride, while the ammonia, hydrazine and nitrogenescape by volatilization. Therefore, titration of the white residue(obtained on evaporation of the condensate) for chloride gives a directmeasure of the chloramine generated. This can be related back to ameasure of the chlorine used to obtain the chloramine yield. There is analternate procedure which is suitable for use when chloramine isactually being consumed by reaction with the alkaloid. The amount ofchlorine used in a run, which may be the limiting reagent quantity foryield calculation, can be measured directly, e.g., by weight of thechlorine cylinder before and after use, or by use of flow meters, Theamount of ammonium chloride retained within the generator isdeterminable by titrating an aliquot of the aqueous solution of all ofthe solid remaining within the chloramine generator after the reactionhas been completed. The chloramine yield, expressed as percent of thetheoretical yield, can then be calculated iromthe formula:

(AB) 200 A where A is the total number equivalents of chlorine passedinto the generator and B is the number of equivalents of chlorideretained within the generator. The chloride content of the generatorthus serves as an indicator of the efiiciency of chloramine formation.

percent= Example 11 A 50 g. portion of tropinone hydrobromide wasdissolved in 200 ml. water. This solution was shaken well with an excessof sodium bicarbonate and thereafter extracted with four 100 ml.portions of CHC1 The solution was dried over anhydrous magnesium sulfateand the filtrate was made up to 850 ml. with additional CHCl Theresulting solution wastreated with 3.8 equivalents of chloramine fromthe generator described in Example I over a period of four hours. Withinminutes a thick precipitate had formed. Two .250 ml. portions ofadditional solvent were added to the mixturev to thin out thisprecipitate. The mixture was allowed to stand overnight and thereafterfiltered to give 26.1 g. of oif-white product. The product comprisedammonium chloride and about 10% N-aminotropinonium chloride. The novelproduct thus obtained can be alternatively described as8-amino-3-ketotropanium chloride. Evaporation of the reaction, filtrategave 22 g. of crude. product which was combined with 2 g. of thealkaloid adduct extracted from the precipitate. The mixed brown oil andsemi-solid thus obtained was washed free of starting base with diethylether and benzene. The purified material appeared as a hygroscopicbrownish resin melting with gas evolution at about 110 C. and turningred at about 150 C. Continued purification gave an offwhite, hygroscopicsolid decomposing with gas evolution at about 136 C. It formed8-amino-3-ketotropanium pier-ate, having a melting point of 185-187" C.when treated with aqueous picric acid. The novel chloride was soluble inwater, ethanol and chloroform. It was insoluble in ether and benzene andrecrystallizable from nitromethane. The preparative reaction is shownbelow in Equation 3. (The carbonyl groups may be reduced to the alcoholof Example IV or alkylated by conventional means.) I

Example 111 A saturated solution of 2,4-dinitrophenylhydrazine in 2 NHCl was added to 50 mg. of the product of Example II in 10 ml. H O. Theaddition resulted almost immediately in the formation of a flocculentorange precipitate. This material was filtered, washed well, dried, andrecrystallized from nitromethane to give yellow-orange flocs of8-amino-3-ketotropanium chloride 2,4-dinitrophenyl hydrazone. This newproduct decomposed at about 210 C. Its preparative reaction is shownbelow in Equation 4.

' Example I V A 20 g. portion of tropine was dissolved in 150 ml. ofchloroform. This solution was treated with chloramine (formed in thegenerator in about a 70% yield from 20 g. of chlorine for approximatelyone hour. The reaction mixture. was allowed to stand overnight.Subsequent filtration gave 30.1 g. of white solid containing 21.9%chloride ion, corresponding to 913% pure 8- amino 3 hydroxytropaniumchloride, melting above 285 C. This new product was soluble in water andethyl alcohol. It was insoluble in chloroform and ethyl acetate. Simplemetathesis gave its phosphate, hexafiuorophosphate, nitrate, chromate,iodide, silicate, and ferricyanide derivatives which were all found tobe water soluble. Conversion in the same manner to the picrate,picrolonate and diliturate gave yellow, white and pale yellowmierocrystalline water-insoluble solids melting at 280 0., above 280 C.and above 280 C. respectively. The preparative reaction of the novelchloramine adduct is shown in Equation 5.

HIO+

A 100 mg. solution of the product of Example IV was dissolved in 10 ml.of water and then treated dropwise alternately with 20% NaOH solutionand an equivalent portion of benzoyl chloride according to the standardSchotten-Baumann reaction; adding four equivalents of benzoyl chlorideand six equivalents of NaOH in all. After all. of the benzoyl chloridehave reacted the pH of the. mixturewas cautiously readjusted to between8 and 8.5- with acetic acid to give a, further precipitate. Subsequentfiltration, followed by thorough washing withcold water, gave about 100mg. of crude 8-aminos3-benzoyloxytropanium benzoate, melting at l62163C. Re? crystallization from water gave a chloride-free product appearingas fine needles. The novel product was recrystallizable from water,soluble in ethanol and insoluble in chloroform. Its preparation is shownbelow in Equation'6.

A 30 g. portion of atropinesulfate; V

(C17H23NO3) 2 4: 2

was dissolved in ofwater. solntionjwas 7 treated with 8-10 g. of sodiumcarbonate and thereafter extracted with two 150 ml. portions ofchloroform. The chloroform extract was dried, filtered and diluted to1000 ml. with additional solvent. The chloroform solution was treatedwith chloramine from the generator (converting 0.006 mole of chlorineper minute to ClNT-I in a 92% yield) for 15 minutes. After standingovernight the reaction mixture gave 11 g. of a white solid precipitatecontaining 29% chloride ion. This analytical result corresponded to a25% yield of pure N-aminoatropinium chloride, melting at 231 C.Fractional precipitation from isopropyl alcohol gave a middle cut ofpure product having the same melting point. The analysis of thismaterial compared with theory as follows: percent Ccalculated- 59.9,found 59.56; percent H calculated 7.39, found 7.26; percent N calculated8.22; found 8.33; and percent Cl calculated 10.4, found 10.4. The novelhydrazinium chloride was found to be soluble in water and ethanol; itwas insoluble in chloroform. When treated with potassiumhexafluorophosphate it formed a water insoluble salt melting at 145 C.By metathesis, the corresponding bromide, sulfamate, phosphate, andnitrate were formed. These novel salts were all water soluble. Thepreparative reaction is shown in Equation 7 below.

om-orr--om n Example VII Concentrated aqueous solutions of 0.001 moleeach sodium barbital and the product of Example VI were mixed andallowed to stand. In the course of two weeks a flocculent whiteprecipitate slowly formed within the mixture. This new product Wasidentified as the 5,5- diethyl barbituric acid salt of theN-aminoatropinium cation, melting at l58l63 C. This same product wasmore readily prepared in better yield by an alternative procedureinvolving refluxing similar solutions in ethanol for half an hourallowing them to cool, followed by subsequent filtration, evaporation todryness, cold water washing and drying. Material thus obtained wasrecrystallized from an ethanol-ethyl acetate mixture to give whitecrystals melting at about 168-170 C. and decomposing at about 175 C.Equation 8 shows the preparative reaction.

The product thus obtained was somewhat soluble in water and appreciablymore soluble in ethanol. It was insoluble in chloroform.

lization of the dried product from an ethanol-ethyl acetate mixture gavea 63% yield of off-white penicillinaminoatropinium salt. This novel andinteresting compound ran clear and evolved gas with darkening at 155 C.on the melting block.

' Example IX A 56.7 g. portion of scopolamine hydrobromide C H NO.HBr.3H O was treated with aqueous sodium bicarbonate and chloroform bythe method described in the previous examples. This treatment gave achloroform solution containing 29 g. of the free base. Chloramination ofthe solution followed by filtration and subsequent work up gave a whitesolid containing 22% chloride ion. Analysis showed this material to beapproximately a 27:73% by weight mixture of ammonium chloride andN-aminoscopolaminium chloride, melting with decomposition andsublimation at about 212 C. From the filtrate was obtained onevaporation in'vacuo 17.3 g. of material, largely unreacted scopolamine,but containing approximately 4 g. additional product. The initialprecipitate was washed well with boiling isopropyl alcohol and ethylacetate to partially remove the ammonium chloride and other products.This treatment resulted in a solvent-insoluble, water-soluble productabout 87% pure, useful in making derivatives. The material was furtherpurified by recrystallization several times from dimethylformamide toget fine needles of pure aminoscopolaminium chloride melting at 206-207"C. with decomposition. Upon analysis, the composition of the purifiedproduct compared with theory as follows: percent C calculated 57.13,found 57.54; percent H calculated 6.28, found 6.53; percent Clcalculated 10.09, found 9.99. When treated with aqueous potassiumhexafiuorophosphate the novel chloride formed a waterinsoluble salt.Metathesis with picric acid gave a waterinsoluble product melting at186-188 C. The chloride itself was poorly soluble in chloroform,somewhat more soluble in isopropyl alcohol, and still more soluble indimethylformamide and nitromethane. It was extremely soluble in water.See Equation 9 below. CHzOH CHCH-CH OgCCCsHs 0 l ens-11: (3 I E H '1H EHCHzOH v CHCH-CH1 02C -CsHs o l HaC-N-NHz 1'1 CI- HCH-- H2 H Example XThe prolonged reaction of hot isopropyl alcohol with solidN-aminoscopolaminium chloride containing about 13% by weight ammoniumchloride impurities in a Example VIII Portions of 0.001 mole each ofpotassium penicillin G and the product of Example VI were dissolved in20 ml. of absolute ethanol. The solution was refluxed for half an hourand allowed to cool. It was subsequently filtered and evaporated todryness in vacuo. Recrystal- A 56.6 g. portion of hyoscyaminehydrdbromide was converted by the procedure described in Example IX to achloroform solution containing 44.3 g. of free base.

Chloramination gave as. an initial precipitate 43.8 -g. of

white solid. Analysis of the crude product showed 19.3% chloride ionwhich-corresponded to about a 16:84 mixture by weight of ammoniumchloride and N-aminoh-yoscyaminium chloride. The crude product melted"at 205 C. By metathesis, it formed a hexafluoroph'os- I, .phate whichmelted at 74--76 C. The filtrate was allowed to stand and 8.5 g. ofadditional white solid precipitated therefrom. This material analyzed9.62% chloride ion which corresponded -to about 92% pure hydra-ziniumchloride. Evaporation of the filtrate gave an additional small quantityof product. The original product 'was recrystallized repeatedly l-from-dimethyliormamide. The purified material melted at 205-207" C. withdecomposition. Its preparativereaction is similar to that given inExample VT, since atropine is the hyoscyamine racemate. The add-uetpurified to the stage where it becomes too hygroscopic for convenienthan- ,dling, -still contained slightly less than 2% ammonium chloride.Elemental analysis confirmed this; calculated :for a 1.7 NH Cl: 98.3%adduct mixture: C, 58.8; H, 7.26; N, 8.51.; Cl, 11 .4. Found: C, 58.6; Il, 7 .10 N, 8.35; C1, 1-1.51. It formed a water insoluble picrate andhexafluorophosphate melting at 7678 C. and -7-8 C. respectively.Metathesis also produced a water soluble iodide which melted at 261 C.with decomposition.

Example XII A 50 g. portion of homatropine hydrobromide was converted tothe free ba'se in about 1000 ml. of chloroform by the proceduredescribed in the previous examples. Chloramination of this solution gaveas an initial precipitate 28.7 'g. of a white solid. On the meltingblock, this material melted at 245 C. with sublimation; by analysis itwas found to contain 22.01% chloride'ion which represented a mixtureofabout 20% ammonium chloride and 80% N-aminohomatropiniumchloride;Evaporation of the filtrate invacuo gave 24 g'. of brownish pasty solid,part of whichmelted at 178" C. Treatment of this material byeth'erextractio'n resulted in an adidtional product which was about 84%pure. By metathesis, it formed an insoluble hexafluorophosphate meltingat 178-182 'C. The product obtained by evaporation of the filtrateappeared to contain a stere'disomer of the product in the initialprecipitate, since this latter material .gave ahexafiuorophosphatemelting at 154 1 C. Evaporation of the ether washesgave about 12% unreacted 'homatropine. Recrystallization of the initialprecipitate from dimeth'ylfo rmamide several resulted in the formationof white needles of N-a'rninohomatropin ium chloride meltingat"abo1'1't-2502'5-l C.

with decomposition. This produ t exhibited thesanie general solubilitycharacteristics as the N-aminohyosoyaminium chloride of Example XI andsimilarly was handled most conveniently as a product containingsomeammonium chloride. 2.5% .ammonium chloride: 97.5% adduct calculated: C,57.3; H, 6.91; N, 9.21; Cl, 12.2. Found: C, 57.2; H, 6.95.; N, 9.02; Cl,12. 2. Treatment of the chloride with saturated aqueous picric acid gavean insoluble dull yellow picrate. After recrystallization from water andaqueous ethyl alcohol, the picrate melted at 1 63164 C. The picratecalculated: C, 50.9; H, 4.85; N, 13.5. Found: C, 50. 8; H, 4.86; N,13.5. The preparative reaction of the picrate is shown below in Equation11.

Example XIII A 26'g.1portion of cocaine was dissolved in chloroform inthe "manner previously described and treated with a large excess ofchloramine from the generator. Analysis of the initial precipitateobtained from this reaction mixture showed the crude material to containabout 82% ammonium chloride and 18% N aminococaninium chloride (8amino-2-carbomethoxy-3-benzoyloxytropanium chloride). Evaporation of thechloroform filtrate gave 27.7 g. of mixed 'nnreaeted baseand roduct. The6.1 g. "of product thus obtained represented 85% conversion based on therecovered amine. Ether extraction of a small portion of the product leftas an ether-insoluble residue, the relatively pure chloramine adduct,melting 'at about 148 C. Metatheis'is resulted in an insoluble 'picratemelting at 65-67" C. Resistance of cocaine to chloramination,demonstrated in replicate runs, may be due to steric factors. Thepreparative reaction of the novel Naminocoeainium'elilorideis shownbelow in E uation 12.

om-wm-cn-oooorn I OOCCt 5 cmni -r treated and evaporated dry twice withisopropyl alcohol,

and extracted with ether to remove benz'oic acid. The resulting materialwas extracted with isopropyl alcohol and the extract evaporated todryness 'to give about; 50 mg. of off-white N-aminoecgoninium chloride(2-carboxy-3-hydroxy-8-aminotropanium chloride). This novel saltdehydrated at about '11'8-121 C. and meltediatfab t 186" C. The productwas soluble in water and ethanol.

Treatment of a concentrated aqueous solution s ot:

um hydroxide gave a trace solid believed to be the correspondingbetaine. See Equation 13 below.

Example XVI A 100 mg. portion of N-aminohyoscyaminium chloride (theproduct of Example XI) and a corresponding amount by weight of calciumo-acetoxybenzoate (sometimes called calcium acetylsalicylate) weredissolved in 30 ml. of Water. The solution was evaporated dry in vacuo,extracted with 450 ml. portion of ether and taken up with 30 ml. ofisopropyl alcohol. This solution was filtered and the filtrate wastreated with 90 ml. of ether and allowed to settle. Subsequentfiltration gave a low yield of N-aminohyoscyaminium o-acetoxybenzoate,appearing as white powder melting at 151-153" C. It was somewhat lesssoluble in water than the product of Example XV.

Example XVII A 100 mg. portion of N-aminoatropinium chloride was mixedwell with 100 mg. of sulfanilamide. -The reaction product was kept at120 to 130 C. for an hour and a half with good but occasional mixing.The material was cooled, washed with three ml. portions of acetone andrecrystallized from ethanol-ethyl acetate mixture to give the novelaminoatropinium salt of sulfanilamide, melting at 131-133 C.

Example XVIII A 0.1% solution of 1,4-po1y(ammonium 2-carbamyl-4-methoxyvalerate) in water (a polymer available commercially as PVM/MAhalfamide) was treated with 0.003 mole of N-aminoatropinium chloride in20 ml. of water. The mole ratio of the reactants corresponded to about 1part of the polymer to /2 part of the hydrazinium chloride. The reactionmixture was stirred well, filtered and washed with water to give about170mg. of the corresponding mixed hydrazinum ammonium salt of thepolymer decomposing at about 210 C.

Example XIX A mixture of 0.2 g. (ca. 0.001 mole) of aminotropiniumchloride, 0.5 g. (ca. 0.002 mole) of benzhydryl bromide and 0.075 g. ofanhydrous sodium carbonate creatinine sulfate and barium chloride.

12 (ca. 0.0007 mole) were stirred in 20 ml. of pyridine at roomtemperature for 16 hours and then at 60 C. for 3 hours additional. SeeEquation 14. The inhomogeneous reaction mixture was evaporated todryness in vacuo without heat and the incompletely solid residue waswashed well with benzene to remove unreacted benzhydryl bromide followedby extraction with cold dry chloroform. Evaporation of the chloroformextract gave a low yield of crude mixed 8-amino-3-benzhydryloxytropaniumchloride and bromide (X) as a thick yellow oil which could not besolidified on chilling, by seeding or scratching. The oil was soluble inwater, ethanol, chloroform, Cellosolve; slightly soluble in acetone,recrystallizable from ethyl acetate and insoluble in carbontetrachloride and dioxane. An aqueous solution gave the dull yellowamorphous picrate melting at 178-181 C.

Hr- H H: 05H: Example XX To a mixture of 0.2 g. aminotropinium chloride,2 ml. pyridine and 10 ml. chloroform there was added dropwise and withvigorous intermittent shaking a solution of 0.25 g. diphenylacetylchloride in 20 m1. anhydrous chloroform. The reaction mixture wasallowed to stand with intermittent shaking for 48 hours. The reaction isshown in Equation 15. The reaction mixture was evaporated to dryness invacuo and the resultant tan solid slurried twice with dry benzene,filtered and air dried. The solid was slurried with 5 ml. of 5% aqueoussodium carbonate, filtered and evaporated to dryness in vacuo.Extraction with isopropyl alcohol and evaporation of the solvent gavetan amorphous 8-amino-3-diphenylacetoxytropanium chloride. The crudeproduct was recrystallized from ethanol-ethyl acetate to give offwhitegranular crystals melting 146-148.5 C. with decomposition. When aboiling aqueous solution was treated with a 10% solution of potassiumiodide, the brownish yellow iodide slowly separated out on cooling asirregular plates melting 191-1925 C. with decomposition.

CH:-CH-CH: 0 00H HaC-N-NH: CH-OCCH Hz---CH- Hz 0H5 Example XXI Tofurther demonstrate the utility of our novel compounds, pharmocologicalstudies were made on N-aminoatropinium chloride, N-aminoscopolaminiumchloride and N-aminohomatropinium chloride. These were tested at variousconcentrations against sub-maximal contractions of guinea pig ileum(isolated smooth muscle) caused by acetylcholine chloride, histaminephosphate, serotonin At a concentration of 25 micrograms (1:4,000,000)all three compounds completely blocked contractions due to acetylcholinebut had no effect on contractions induced by histamine, serotonin orbarium. This is indicative of strong antispasmodic action. At one gamma(1:100,000,000)', N-aminohomatropinium chloride had lost its activity;at one-tenth gamma (1:1,000,000,000), N-aminoscopolza minium chloridewas still moderately efiective. This wherein R and R taken individuallyare hydrogen; R and R taken collectively are oxygen completing theoxirane 14 ring; R taken alone is a member selected from the groupconsisting of hydroxyl, phenoxy and diphenloweralkoxy; R takencollectively with R form a carbonyl oxygen completing the carbonylgroup; R taken alone is hydrogen; and A* is a pharmaceuticallyacceptable anion.

2. Compound according to claim 1 wherein R and R are hydrogen, R and Rare carbonyl oxygen completing the carbonyl group and A is chloride.

3. Compounds according to claim 1 wherein R, R and R are hydrogen, R ishydroxyl and A is chloride.

4. Compounds according to claim 1 wherein R, R and R are hydrogen, R isdiphenloweralkoxy and A is chloride.

5. 8-amino-3-ketotropanium chloride.

6. 8-amino-3-hydroxytropanium chloride.

7. 8-amino-3 -benzhydryloxytropanium chloride.

8. 8-amino-3-benzhydryloxytropanium bromide.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No.2,948,730 August 9 1960 Bernard Rudner et ale certified that errorappears in the above numbered pat- It is hereby t the said LettersPatent should read as ent requiring correction and the corrected below.

Column l2 lines 55 to .58 the formula should appear as shown belowinstead of as in the patent:

Signed and sealed this 31st day of October 1961.,

(SEAL) Attest:

ERNEST W, SWIDER DAVID L, LADD Attesting Officer Commissioner of Patents

1. COMPOUNDS HAVING THE GENERAL FORMULA: